RNA Damage-induced Viral Mimicry as a Mechanism of Cisplatin Cytotoxicity in Ovarian Cancer

Saige Daines

Mentor: Dr. Sreejith Nair, Department of Oncology, Georgetown University Medical Center.

Date/Time: August 21st, 2025, 2025.

Abstract: Cisplatin is a first-line chemotherapeutic agent used to treat high-grade serous ovarian cancer (HGSOC). Cisplatin is a DNA-alkylating agent and exerts its cytotoxic effects primarily by inducing DNA damage and triggering apoptosis. However, high off-target toxicity and clinical resistance present a large barrier to the effectiveness of cisplatin as a treatment. The mechanisms underlying cisplatin cytotoxicity and resistance are not fully understood. Extensive biochemical evidence shows that cisplatin can also interact with cellular RNA in addition to DNA. Emerging data from our lab indicate that cisplatin engages with RNAs through specific structural elements, altering RNA structure, processing, and stability. Our data also shows that in cancer cells, cellular platinum accumulates ~ 7-fold more in RNA compared to DNA. Altogether these data demonstrate that RNA is the major off-target molecule of cisplatin. However, the biological significance of cisplatin-RNA interaction remains largely unknown. This project investigates the hypothesis that one of the biological outcomes of cisplatin-RNA accumulation is that it induces RNA damage and activates a viral mimicry response, a type of innate immune pathway triggered by double-stranded or misprocessed RNA that mimics a viral infection.

I applied an integrative multi-omics analysis (RNA-sequencing, proteomics, chromatin accessibility) to test this hypothesis. Combined with bioinformatic analysis of DepMap and TCGA datasets, we demonstrate that cisplatin treatment of ovarian cancer cells induces upregulation of antiviral interferon-stimulated genes (ISGs) such as ISG20, IFIT3, and SOCS1, consistent with activation of RNA-sensing pathways. Chromatin accessibility analyses showed an increase in openness at regulatory elements associated with RNA- and antiviral-response genes (e.g., TLR3), while proteomic data confirm post-transcriptional upregulation of key ISGs. Importantly, sensitive ovarian cancer cell lines exhibit a stronger ISG and apoptotic response, whereas resistant cell lines were primed with NF-κB inflammatory innate immune pathways. Clinical relevance is supported by survival analysis of TCGA data, where higher expression of antiviral and RNA-processing genes correlates with improved patient outcomes.

These findings suggest that cisplatin-induced cytotoxicity is mediated not only by DNA damage but also by an innate immune viral mimicry response, while resistance is conferred through a pro-survival inflammatory innate immune response. This dual mechanism may underlie differences in treatment sensitivity across patients. Our results highlight the potential of targeting RNA-sensing pathways to enhance cisplatin cytotoxicity and overcome resistance in ovarian cancer.